I. Field of the Invention
The present invention relates to 4'-phosphate derivatives of epipodophyllotoxin glucosides, to their antitumor use, and to pharmaceutical compositions containing these new agents.
II. Description of the Prior Art
Etoposide (VP-16, I) and teniposide (VM-26, II) are clinically useful anticancer agents derived from the naturally occurring lignan, podophyllotoxin (III): the class of compounds including etoposide and teniposide is sometimes referred to as 4'-demethylepipodophyllotoxin glucosides. Etoposide and teniposide are active in the treatment of a variety of cancers including testicular, small cell lung, ovarian, breast, thyroid, bladder, brain, non-lymphocytic leukemia, and Hodgkin's disease.
Compounds I and II, and the method for producing them are disclosed in U.S. Pat. Nos. 3,408,441 to Wartburg et al and 3,524,844 to Keller-Juslen et al. The compounds disclosed therein, in particular etoposide and teniposide, serve as starting material for our preparation of epipodophyllotoxin glucoside 4'-phosphate derivatives of the present invention. ##STR1##
Phosphorylation of therapeutic agents containing a hydroxyl group has been used as a means for drug latentiation; the phosphorylated derivatives may then be cleaved in vivo by a phosphatase to liberate the active parent molecule. A brief discussion of phosphates as potential prodrugs is included in the review article entitled "Rational for Design of Biologically Reversible Drug Derivatives: Prodrugs" (Sinkula and Yalkowsky, J. Pharm Sci., 1975, 64:181-210 at 189-191). Examples of phosphates of known antitumor agents include camptothecin (Japan Kokai No. 21-95,394 and 21-95,393, Derwent Abst. No. 87-281016 and 87-281015, respectively) and daurorubicin (U.S. Pat. No. 4,185,111).
Podophyllotoxin phosphate disodium salt IV was prepared by Seligman et al. However, the phosphate was not hydrolyzed by prostatic acid phosphatase and did not show reduced toxicity over the parent podophyllotoxin (Cancer Chemotherapy Reports Part I, 1975, 59:233-242). ##STR2##
The present invention provides phosphate esters of 4'-demethylepipodophyllotoxin glucosides which are active antitumor agents. In particular, the dihydrogen phosphate of 4'-demethylepipodophyllotoxin glucosides and salts thereof are highly water-soluble thus providing a superior pharmaceutical advantage over the current therapeutic agents of this class, etoposide and teniposide, which have minimal water solubility.